Like the two faces of Janus, antibodies can be a gateway to anti-microbial immunity or to autoantibody- associated disease. The recent successful use of anti-CD20 to treat patients with autoimmune dyscrasias has re-focused attention on the role of B cells as therapeutic targets. Mature B cells become antibody secreting plasma cells through a complex process that begins in the germinal center and involves alterations in multiple transcription factors. Work from this laboratory has identified a new player in B cell activation and differentiation, namely the novel gene, Faim. FAIM is unique; it is highly evolutionarily conserved, yet does not contain sequence homology, or structural homology, with any other protein. In B cells FAIM acts as a force multiplier. It boosts CD40 signaling by enhancing CD40L-stimulated increases in NF-:B and IRF4, and, it enhances the CD40L-stimulated decline in BCL-6. As expected from the extra increase in IRF4 and decline in BCL-6 (as well as its location in the germinal center) FAIM overexpression augments the plasma cell compartment in chimeric mice. FAIM expression is stimulated by IRF4 and so once triggered FAIM is involved in a feed-forward positive re-inforcing mechanism. The long term objective of this proposal is two-fold: to understand normal B cell biology focusing on how resting B cells become effectors, and to determine the points at which these processes go awry resulting in autoantibody production and autoimmunity. The near term objective of this work is to define the role of FAIM in facilitating immunity and regulating autoimmunity, with the goal of identifying a new therapeutic target. The specific aims of this proposal are to: 1) conduct a careful molecular structure/function analysis to identify and characterize the unique FAIM effector motif; and, 2) evaluate the influence of FAIM on the quality and selection of antibody produced in a model normal immune response, and on checkpoint integrity in a model system of spontaneous autoantibody production, and elucidate the physiology of FAIM expression in the germinal center. The results of this work are highly likely to provide completely new and fundamental information about how signaling in B cells is promoted, and about how plasma cell differentiation is regulated. Moreover, the recent finding by other investigators (unpublished) that SNPs proximal to, and within, the FAIM sequence are strongly associated with human lupus disease indicates that the mechanisms revealed by this study are highly likely to be relevant to understanding clinical autoimmunity and may provide a new target for therapeutic manipulation. PUBLIC HEALTH RELEVANCE: Antibodies are proteins in the blood that are made by B lymphocytes, which are a kind of white blood cell. Antibodies bind to and help defeat bacterial and viral infections. However, antibodies are not always beneficial; sometimes B lymphocytes make antibodies against self, and these autoreactive antibodies, or autoantibodies, can cause serious autoimmune diseases such as system lupus erythematosus. Recently we found new and important activities produced by a gene that we discovered 10 years ago. This gene, termed FAIM, makes B cells hyperresponsive to some kinds of activation signals and increases the number of antibody producing cells. This gene is fascinating because it is found throughout evolution in both higher and lower organisms (even sponge has a similar gene), but its mechanism of action is unknown. We have found that FAIM is a force multiplier for B lymphocyte responsiveness and development into antibody producing cells. As such, FAIM is likely to play a role in autoimmune disease. Our goal in this work is to determine: how FAIM affects B lymphocytes by identifying the active region of the protein, whether effect of FAIM on antibody producing cells alters which cells produce antibody, and whether FAIM influences the level of spontaneous autoantibodies during autoimmune disease. If our work is successful, we will identify a new molecular target through which it should be possible to regulate B cell activity and antibody production, up to treat immune deficiency, and down to treat autoimmune disease.